Amino Acid Transport and the Biology of Human Gliomas

本建议旨在为恶性神经胶质源性脑肿瘤（胶质瘤）患者提供合理的治疗方法。神经胶质瘤是最难治疗的癌症之一，典型症状包括顽固性头痛和癫痫发作。这些癫痫发作源于肿瘤相关的“瘤周”脑，在低级别胶质瘤中尤其常见，高达90%的患者表现为“瘤周癫痫”，通常难以有效治疗。该基金先前资助周期的中心假设认为，癫痫发作是由神经胶质瘤释放谷氨酸到瘤周大脑引起的，导致瘤周区域异常的神经元谷氨酸受体激活，随着时间的推移，谷氨酸引起兴奋毒性神经元丢失，从而为肿瘤扩张腾出空间。据推测，谷氨酸作为胱氨酸摄取到肿瘤细胞的强制性副产物通过xc-胱氨酸-谷氨酸交换系统释放。这种转运蛋白可以用磺胺硫氮嗪来抑制，磺胺硫氮嗪是一种临床批准的治疗炎症性肠病（克罗恩病）的药物。本提案将进行临床前研究，旨在证明系统xc-活性、肿瘤周围癫痫发作和肿瘤生长之间的机制联系。如果成功，这些研究将支持未来临床使用磺胺氮嗪治疗恶性胶质瘤患者，这些患者迫切需要更好更有效的治疗方法。

This proposal has the objective to develop a rational treatment approach for patients with malignant glial-derived brain tumors (glioma). Gliomas and are among the most difficult cancers to treat and typical symptoms include intractable headaches and epileptic seizures. These seizures arise from tumor associated "peritumoral" brain and are particularly common in low grade gliomas where up to 90% of patients present with "peritumoral epilepsy" that is often refractory to effective treatment. The central hypothesis developed from the previous funding cycle of this grant posits that seizures are caused by the release of glutamate from gliomas into the peritumoral brain, causing abnormal neuronal glutamate receptor activation in the peritumoral region, and, over time, glutamate causes excitotoxic neuronal loss thereby vacating space for tumor expansion. It is hypothesized that glutamate is released as an obligatory by-product of cystine uptake into tumor cells via the system xc- cystine-glutamate exchanger. This transporter can be pharmacologically inhibited using Sulfasalazine, a clinically approved drug for the treatment of inflammatory bowl disorder (Crohn's). This proposal will perform preclinical studies aimed at demonstrating a mechanistic link between system xc- activity, peritumoral seizures and tumor growth. If successful, these studies will support the future clinical use of sulfasalazine to treat patients with malignant glioma who are in desperate need for better more effective treatments.